Groundwater is a strategic resource, which is experiencing a growing threat of contamination worldwide. This study aimed to assess the vulnerability of the groundwaters in the basins of the rivers Gala, Tenguel, and Siete in the Ponce Enriquez mining area, considering as a hypothesis that anthropogenic activities (mainly mining and agricultural) conducted in the area generate a high risk of contamination. Vulnerability to contamination was quantified using the DRASTIC and GOD methods. In addition, the risk of contamination (Rc) was calculated considering the vulnerability index (I_V) and the danger index (I_P). Geographic information system (GIS) environment was used for the spatial analysis and the generation of vulnerability maps. The DRASTIC method showed that the negligible-to-low vulnerability category was predominant (50.7% of the area), followed by moderate vulnerability (25.6%), and high-to-extreme vulnerability (23.7%). Regarding the GOD method, the low and medium vulnerability categories were predominant in 41.4% and 27.5% of the area, respectively. Both methods agree that the center area, where the mining activities are located, has a vulnerability ranging from negligible to moderate. The I_P was low in the eastern zone (58.7 km²) and ranged from moderate (426.2 km²) to high in the central and western zones (371.1 km²), where mining activities predominate. The R_C revealed that 20% of the study area corresponded to a high contamination index; from which, 87% comes from agricultural activities, 9% from mining activities, and 4% due to shrimp farms and urban areas. This is the first study that evaluates the vulnerability to the contamination of groundwater in a mining area of Ecuador. The results of this research can serve as a baseline for future research, since the methodology used provides information on the priority areas for the protection of aquifers, considering the current land use in the study area.